Glioblastoma multiforme (GBM) is the most malignant and common form of primary brain tumor in adults. Despite every effort to treat this disorder using multi-disciplinary approaches (i.e. surgery, radiation, and chemotherapy), recurrence is inevitable with poor outcomes. The pathophysiology of GBM remains incompletely understood, and in particular, little is known regarding what features of glioma cells facilitate local recurrence. Interestingly, a small population of cells in GBM has been identified that are able to initiate brain tumors at low cell numbers. These brain tumor-initiating cells are thought to be involved in tumor progression, resistance to adjuvant therapies, and might even represent the cell of origin for these tumors. A better understanding of the biology of this tumor-initiating cell population could lead to novel therapies targeting the most problematic cell population in these tumors. Ongoing work in the Parsa laboratory has identified for the first time that the complement pathway, traditionally thought to be a mediator of cellular destruction and immunity, may be involved in GBM cell proliferation. The goal of this proposal is to study the impact of complement component C3 activation on the brain tumor-initiating cells in human GBM. Using gliomas resected from patients undergoing surgery, we plan to study a brain tumor-initiating cell population as defined by the marker CD133. We will analyze the impact of C3 activation, C3a generation, and C3a receptor activation on the CD133+ cells within the context of tumor growth and invasion. Given the availability of clinical grade complement inhibitors, a potential role for the complement pathway in GBM progression has translational benefit towards novel therapy. PUBLIC HEALTH RELEVANCE: GBM is a highly aggressive neoplasm which leads to rapid progression of neurologic impairment and death. Patients experience a significant burden physically, emotionally, and financially during the treatment course. Given the general lack of effective adjuvant therapies, exploring novel therapeutic targets is warranted to develop new treatment strategies to treat GBM proliferation and prevent recurrences. We hypothesize that a novel pathway of tumor progression, the complement system, drives GBM proliferation and invasive potential and that a better understanding of these mechanisms may lead to new therapeutic modalities. Achieving the goals of this proposal would provide the scientific foundation for a new type of adjuvant therapy for glioma patients.